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. 2023 Apr 12:12:e82674.
doi: 10.7554/eLife.82674.

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

Mark Gormley  1   2 , Tom Dudding  2 , Steven J Thomas  2 , Jessica Tyrrell  3 , Andrew R Ness  4 , Miranda Pring  2 , Danny Legge  5 , George Davey Smith  1 , Rebecca C Richmond  1 , Emma E Vincent #  1   5 , Caroline Bull #  1   5
Affiliations

Evaluating the effect of metabolic traits on oral and oropharyngeal cancer risk using Mendelian randomization

Mark Gormley et al. Elife. .

Abstract

A recent World Health Organization report states that at least 40% of all cancer cases may be preventable, with smoking, alcohol consumption, and obesity identified as three of the most important modifiable lifestyle factors. Given the significant decline in smoking rates, particularly within developed countries, other potentially modifiable risk factors for head and neck cancer warrant investigation. Obesity and related metabolic disorders such as type 2 diabetes (T2D) and hypertension have been associated with head and neck cancer risk in multiple observational studies. However, adiposity has also been correlated with smoking, with bias, confounding or reverse causality possibly explaining these findings. To overcome the challenges of observational studies, we conducted two-sample Mendelian randomization (inverse variance weighted [IVW] method) using genetic variants which were robustly associated with adiposity, glycaemic and blood pressure traits in genome-wide association studies (GWAS). Outcome data were taken from the largest available GWAS of 6034 oral and oropharyngeal cases, with 6585 controls. We found limited evidence of a causal effect of genetically proxied body mass index (BMI; OR IVW = 0.89, 95% CI 0.72-1.09, p = 0.26 per 1 standard deviation in BMI [4.81kg/m2]) on oral and oropharyngeal cancer risk. Similarly, there was limited evidence for related traits including T2D and hypertension. Small effects cannot be excluded given the lack of power to detect them in currently available GWAS.

Keywords: Mendelian randomization; genetics; genomics; head and neck cancer; human; metabolic traits; obesity; oral cancer; oropharyngeal cancer.

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Conflict of interest statement

MG, TD, ST, JT, AN, MP, DL, GD, RR, EV, CB No competing interests declared

Figures

Figure 1.
Figure 1.. Directed acyclic graph (DAG) depicting Mendelian randomization applied to this study.
Genetic variants (G) can act as proxies or instruments to investigate if an exposure (X) is associated with a disease outcome (Y). Causal inference can be made between X and Y if the following conditions are upheld. (1) The genetic variants which make up the instrument are valid and reliably associated with the exposure (i.e., the ‘relevance assumption’); (2) There is no measured or unmeasured confounding of the association between the genetic instrument and the outcome (i.e., the ‘exchangeability’ assumption); (3) There is no independent pathway between the genetic instrument and the outcome, except through the exposure (i.e., the ‘exclusion restriction principle’).
Figure 2.
Figure 2.. Mendelian randomization results of genetically proxied metabolic disorders with risk of oral and oropharyngeal cancer including sensitivity analyses in GAME-ON.
Oral and oropharyngeal cancer combined n = 6034, oral cancer n = 2990 and oropharyngeal cancer n = 2641. Abbreviations: IVW, inverse variance weighted; OR, odds ratio with 95% confidence intervals; BMI, body mass index; WC, waist circumference; WHR, waist–hip ratio; T2D, type 2 diabetes mellitus; FG, fasting glucose; FI, fasting insulin; HbA1c, glycated haemoglobin; SBP, systolic blood pressure; DBP, diastolic blood pressure. OR are expressed per 1 standard deviation (SD) increase in genetically predicted BMI (4.81 kg/m2), WC (0.09 unit), WHR (0.10 unit), T2D (1-log unit higher odds of T2D), FG (1-log unit increase in mmol/l fasting glucose), FI (1-log unit increase in mmol/L fasting insulin), HbA1c (1-log unit % higher glycated haemoglobin), SBP (1 unit mmHg increase), and DBP (1 unit mmHg increase).
Figure 2—figure supplement 1.
Figure 2—figure supplement 1.. Power calculations for oral and oropharyngeal analyses in GAME-ON.
α set at 0.05.
Figure 2—figure supplement 2.
Figure 2—figure supplement 2.. Forest plots showing Mendelian randomization results for genetically proxied body mass index (BMI) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 3.
Figure 2—figure supplement 3.. Forest plots showing Mendelian randomization results for genetically proxied waist–hip ratio (WHR) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 4.
Figure 2—figure supplement 4.. Forest plots showing Mendelian randomization results for genetically proxied waist circumference (WC) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 5.
Figure 2—figure supplement 5.. Forest plots showing Mendelian randomization results for genetically proxied type 2 diabetes mellitus (T2D) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 6.
Figure 2—figure supplement 6.. Forest plots showing Mendelian randomization results for genetically proxied glycated haemoglobin (HbA1c) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 7.
Figure 2—figure supplement 7.. Forest plots showing Mendelian randomization results for genetically proxied fasting glucose (FG) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 8.
Figure 2—figure supplement 8.. Forest plots showing Mendelian randomization results for genetically proxied fasting insulin (FI) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 9.
Figure 2—figure supplement 9.. Forest plots showing Mendelian randomization results for genetically proxied systolic blood pressure (SBP) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 10.
Figure 2—figure supplement 10.. Forest plots showing Mendelian randomization results for genetically proxied diastolic blood pressure (DBP) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Effect estimates on oral and oropharyngeal cancer are reported on the log odds scale.
Figure 2—figure supplement 11.
Figure 2—figure supplement 11.. Scatter plot for body mass index (BMI) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 12.
Figure 2—figure supplement 12.. Scatter plot for waist circumference (WC) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 13.
Figure 2—figure supplement 13.. Scatter plot for waist–hip ratio (WHR) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 14.
Figure 2—figure supplement 14.. Scatter plot for type 2 diabetes mellitus (T2D) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 15.
Figure 2—figure supplement 15.. Scatter plot for glycated haemoglobin (HBA1c) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 16.
Figure 2—figure supplement 16.. Scatter plot for fasting glucose (FG) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 17.
Figure 2—figure supplement 17.. Scatter plot for fasting insulin (FI) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 18.
Figure 2—figure supplement 18.. Scatter plot for systolic blood pressure (SBP) with risk of combined oral and oropharyngeal cancer in GAME-ON.
Figure 2—figure supplement 19.
Figure 2—figure supplement 19.. Scatter plot for diastolic blood pressure (DBP) with risk of combined oral and oropharyngeal cancer in GAME-ON.
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  • doi: 10.1101/2022.08.10.22278617

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